Novel [nitric acid ester] derivatives of nicotinic acid



United States Patent ()fifice 3,692,634 Patented June 4, 1963 3,l 92,634 NOVEL [NITRIC ACID ESTER] DERHVATWE F NHCUTINIC ACID Alfred Halpern, Great Neck, N.Y., assignor to Synergistics, Inc, New York, N.Y., a corporation of New York No Drawing. Filed Aug. 24, E59, Ser. No. 335,406

' Claims. (Ql. zen-295.5

The present invention relates to novel nitric acid ester derivatives of nicotinic acid and their method of preparation. In particular, it describes the bis-nitric acid ester of nicotinic acid-bis (beta -hydroxyethyl) amide, which may also be referred to as nicotinic acid-bis-(beta-nitroethyl)-amide; its acid addition salts as well as the salt, the nitric acid ester of bis-(beta-hydroxyethyl)amine nicotinate, which may also be referred to as, bis-(beta-nitroethyl)amine nicotinate and the chemical processes for their synthesis.

An object of this invention is the provision of new and improved therapeutic agents which may be used to relax blood vessels, thereby causing a vasodilatation, with consequent lowering of the systemic blood pressure as well as improving the circulation of blood through the tissues.

The role of v asodi'la-tation in modern medical practice is becoming increasingly more important since it has been determined that many serious diseases are caused by circulatory deficiencies. These deficiencies may arise from a spasm (or a blockade) of conducting blood vessels, which reduces the volume of blood coursing through the tissues which these vessels supply. While the immediate efiect of a reduction of the blood supply to an area may be evidenced through pain and cyanosis, this state, if allowed to persist, will result in gangrene and loss of a limb. Should this reduced blood supply occur in a vital area, such as the blood supply of the heart muscle or the blood supply of the brain, 'the immediate elfects may be total incapacitation and very often death.

The method of treatment of such circulatory disturbances involves the institution of appropriate vasodil-ating measures, either by pharmacologic means or through surgery. Because of the general widespread nature of occlusive artertial disease, the surgical approach is of limited value and has been found useful in relatively few types of these pathologic entities. In addition, the inherent risks of surgery to a patient with an already deteriorating vascular system further detracts trom this manner of therapy. Conservative medical management remains the method of choice for approaching problems of diminished blood circulation resulting :trom occlusive vascular disease. Vasodilating drugs have been widely employed for this purpose although with varying success.

Among the drugs utilized for vasodilatation are included nicotinic acid; its derivatives, and the inorganic and organic nitrates. Both of these classes of compounds have many specific advantages, as well as limitations (in the scope of their application to vascular medicine). Thus, it is found that the action of nicotinic acid is fleeting and, since short transient vasodilatation is of little value in the over-all management of these disease entities, continued administration of nicotinic acid therapy becomes a necessity. This is both impractical and uneconomic for the patient. Another limitation of the use of nicotinic acid is its predominant action on the vessels of the skin, resulting in both a feeling of discomfort and an onset Of a disturbing reddening of the skin which has been noted as a blush. Furthermore, uasodilatation of the surface vessels is only of ancillary importance to the over-all therapeutic program.

The nitrates exert a direct vasodilating action on the muscle of the arteries. While the action of the nitrates is exerted on the deeper vessels of the muscles rather than on the skin alone, serious side reactions, such as profound lowering of the flood pressure, as well as direct action on the heart muscle, require that these drugs be used very cautiously. Severe headache is also common for the patient who takes nitrates in larger dosages, and this limits the amount of the drug which may be administered, consequently may prevent a patient from receiving the optimal therapeutic dosage. Furthermore, the duration of the pharmaocologic effects of a nitrate compound is runpredictable, with certain nitrates causing a short and fleeting efiect (as for example, nitroglycerin), while others, derived from closely relating materials, cause a rather prolonged effect (such as erythritol tetran-itrate). A tolerance to nitrate drugs is known to develop and this requires increasing dosage to sustain its effect.

In contrast to these problems associated with the use of the older vasodilating drugs, the products or the present invention exert a uniform vasodilating effect on the blood vessels situated both in the skin and in the deep muscles. The compounds are non-toxic and highly effective as vasodilati-ng drugs capable of causing a rapid onset of action, which extends over a sufi-lcient period of time to permit a continuous therapeutic action by proper spacing of dosage administration. These agents may be compounded into tablets or liquid preparations suitable for use in both veterinary and human medicine.

The bis-nitric acid ester of nicotinic acid-bis-(beta-hydroxyethyl)amide is obtained as a result of the interreaction between nicotinyl acid chloride and the bis-nitric acid ester of diethanolamine, carried out under anhydrous conditions in the presence of a hydrogen chloride acceptor, for example, triethyl amine. The reaction may be pos tulated to proceed as fol-lows:

CHI-CH -ONO2 z I 0001 onou HN a)a CHz-CHz-ONOa OHPOHZONOI CON I CH2 CH2ONO Bis-nitric acid ester of nicotinic acid-b-is-(beta-hydroxyethyl)amide is a crystalline compound, melting at 147 to 149 C., which is diflicultly soluble in isoprop'anol, but is soluble in methanol. This compound, obtained in the monohydrate form, has an empirical formula of C H O N l-I O and the molecular weight of 318.2. It analyzes for carbon, hydrogen, and nitrogen in good agreement with the theoretical values which are calculated as 37.74 percent carbon, 4.43 percent hydrogen, and 17.61 percent nitrogen. The analysis of the product obtained by the method described shows that it contains carbon, 38.37%; hydrogen, 4.43%; and nitrogen, 17.94%. The structural formula of the base may be postulated as:

CHzCH20NO5 CON CHr-CHzONOa N The nicotinic acid salt of the bis-nitric acid ester of diethanolamine although having the same empiric formula (C H O N as the amide monohydr-ate exhibits different chemical and pharmacologic properties. The major and significant difference between the two resides in the manner and site of action of these drugs.

The salt, which is a polar compound, is dissociated at the pH of physiologic fluid so that rapid tissue availability of the nicotinic acid moiety results, when the compound reaches the physiologic pH range of the blood stream. This earlier availability of nicotinic acid permits the vasodilatation of the vessels of the skin to precede that of the deeper vessels which results from the nitric acid ester of diethanolamine portion of the molecule. Thus, the more fleeting vasodilatation of the nicotinic acid is supported and sustained by the onset of secondary action of the nitrates. This synergism of physiologic etfects is extremely important since it permits a more etfective dual approach to the problem of obtaining an increased blood supply to surface areas and consequently is important to the treatment of cold induced vaso-constrictive disorders of the skin, such as Raynauds disease, acrocyanosis, chilbains and the like. Since the nicotinic amide is much more resistant to cleavage than is the polar bond of the salt, the amide" compound begins its principal actions through the nitrate moiety on the deeper vessels. In the course of its metabolic degradation, however, the pharmacologic activity is transferred to the nicotinic acid portion and the vessels of the skin. Thus, virtually opposite pathways of pharmacologic activity are obtained through the administration of these separate compounds, although a similar end-result of an increased blood supply to the tissues is obtained. It is just these differences in the mechanism of therapeutic action that bestow special significance to each of these compounds in therapy. Each compound has an important and valuable place in supplying a special pharmacologic effect for a particular patient requirement.

The nicotinic acid salt of the bis-nitric acid ester of diethanolamine is obtained by reacting stoichiometric equivalents of nicotinic acid and bis-nitroethanolamine in an alcoholic solvent. The desired compound, obtained by precipitation with ether, is a crystalline, yellow colored solid melting at 130 to 131 C. The compound is obtained as a monohydrate corresponding to the formula C H O N -I-1 O, with a molecular weight of 336.26 and has a theoretical nitrogen content of 16.66% (Found percent nitrogen, 16.50%). The following structure may be postulated for the salt:

II CHz-CHz-ONO:

When it is desired to utlize these novel nitric acid alkyl ester derivatives of nicotinic acid in clinical practice, they may be compounded into tablets, capsules and solutions both for oral and parenteral administration. These pharmaceutical preparations are prepared so that each unit will supply a dose of from 25 to 50 mg. of the active compound and may be administered several times daily in accordance with the individual patients needs.

The following examples describe the products of my invention and the processes for obtaining them:

CHz-CH2ONO2 Example 1 To 3.5 grams of nicotinyl chloride hydrochloride dissolved in 25 cc. of dry chloroform, is added 2.0 grams of triethylamine in the cold. This mixture is slowly added, with constant stirring, to a mixture of 5.0 grams of nitric acid ester of diethanolamine nitrate (Mem. Poudres. 35:117 (1935)) and 4.0 grams of triethylarnine in 50 cc. of dry chloroform, contained in a flask fitted with a moisture trap, a delivery tube and a stirring device. The temperature of the reacting mixture is maintained below 0 C., and the reaction allowed to proceed until no further evolution of hydrogen chloride occurs. The stirring is continued while the reaction mixture is allowed to warm to room temperature and then maintained at room temperature for an additional two hours. The resultant precipitate is filtered and consists of the hydrochloride acid salt of the bis-nitric acid ester of diethanolamine (melting point 145 C. and may be identified by mixed mel ing point techniques as well as chloride analysis).

The chloroform solution is extracted several times with ice water, and the solvent evaporated under diminished pressure. The residue is dried in vacuo over phosphorus pentoxide and consists of a dark-red oil which readily dissolves in methanol and ethanol although after standing (for approximately 12 hours) the ethanol solubility is greatly diminished. The oil is boiled with isopropanol and a large insoluble fraction remains which is slightly soluble in methanol. The isopropanol extract is filtered and the filtrate set aside to crystallize.

The crystalline precipitate which develops in the isopropanol extract melts between 135 and 139 C. This crystalline material is only slightly soluble in boiling isopropanol but can be readily recrystallized from methanol, after which, it melts at 147 to 149 C. The pure, crystalline material is the bis-nitric acid ester of nicotinic acidbis-(beta-hydroxyethyl)-arnide (monohydrate) with an empirical formula of C101'I140g114 and a molecular weight of 318.2. It analyzes for carbon, hydrogen and nitrogen as 38.3% carbon; 4.43% hydrogen; and 17.94% nitrogen. The theoretical content of these atoms are carbon, 37.74%; hydrogen, 4.43%; and nitrogen, 17.61%. This compound is the monohydrate corresponding to the following structural formula:

CHzCH2ON0l CON Example 2 To 3.5 grams of the bis-nitric acid ester of diethanolamine dissolved in cc. of absolute ether and contained in a glass vessel fitted with a delivery funnel, a moisture trap, and a stirring device, and cooled to a temperature of less than 5 C., is added 2.5 grams of nicotinyl chloride dissolved in 25 cc. of absolute ether. A light yellow precipitate forms immediately which after 15 minutes of stirring is vacuum filtered at room temperature and washed with dry ether. The dried precipitate is ground with 30 cc. of methanol and the mixture heated to boiling and allowed to crystallize by cooling. The crystalline material obtained in this manner melts at 153-155 C. and is the hydrochloride of the bis-nitric acid ester of nicotinic acid-bis- (beta-hydroxyethyl -amide.

The base material may be obtained by neutralization with sodium carbonate solution, although this is not necessary since the hydrochloride salt of the amide may be utilized in therapy.

Should it be desired to utilize other pharmacologieally acceptable acid addition salts than the hydrochloride salt of the base, then these may be formed from the base compound by treatment with the appropriate acid in either aqueous or alcoholic media. Thus, through the utilization of either hydrogen bromide, sulfuric acid or dilute nitric acid, the respective acid salts of the base would be obtained. Other pharmacologically acceptable acid addition salts may be similarly formed. Such salts may also be obtained by metathesis between the hydrochloride and a salt of the desired acid. However, other than from the viewpoint of different solubility characteristics and physical properties, these acid salts impart no new therapeutic properties.

Example 3 A mixture of 1.5 grams of the bis-nitric acid ester of diethanolamine and 0.95 gram of nicotinic acid in 10 cc. of methanol are heated for 15 to 30 minutes to dissolve the components. The solution is allowed to cool slowly to room temperature and set aside to stand overnight. The dark-red solution is then mixed with suflicient ether to just initiate precipitation and the mixture cooled. The precipitate is filtered; dried and is found to melt (with decomposition) over a range of from to C. This dried impure salt is recrystallized several times from a mixture of ethanol and ether until a light-yellow, crystalline flake is obtained which melts sharply at 130 to 131 C. This compound is the monohydrate of nicotinic acid salt of the bis-nitric acid ester of diethanolamine and has a molecular weight of C H O N corresponding to the following structural formula:

H OHPCHsONOz The compound analyzes for nitrogen, as follows: Calculated percent nitrogen, 16.66%; found percent nitrogen, 16.50%.

Example 4 In place of the nicotinyl chloride, described in Example 2, may be substituted nicotinyl bromide, in stoichiometric-ally equivalent amounts and the remainder of the process carried out as described in Example 2. The resultant product is the hydrobromide salt, in place of the hydrogen chloride salt. Similarly, other pharmacologically acceptable cations may be substituted for the chlorine atom and other pharmacologically acceptable acid salts secured directly as the reaction product. In each case the base may be obtained by neutralization of the salt.

Example 5 When it is desired to utilize for therapy the bis-nitric acid ester of nicotinic acidbis-(beta-hydroxyethyl) amide, or its acid salts, or the salt, bis-(beta-nitroethyl)amine nicotinate, as a tablet or a capsule, the concentration of active material per unit dose is adjusted so that it contains from 25 to 50 mg. of active material and is administered according to the patients needs.

Tablets may be prepared by granulating the active materials with a diluent, as for example, milk sugar, in ratio of at least one part active material to 9 parts of diluent. The use of the well-known binders or lubricants which are essential to good tablet manufacture also may be added in appropriate concentrations as is well known to the art, in accordance with the particular tablet requirements. After the granulation step, in the preparation of tablets, the mixture is compressed into tablets each containing from 25 to 50 mg. of active material. These tablets are then administered to the patient in accordance with his own needs dependent upon the age of the patient and the severity of the disease.

The granulating mixture which is obtained prior to compressing of tablets may be filled into gelatin capsules, utilizing the same unit range of dosage (viz. 25 to 50 mg. of active material per capsule). These capsules are administered to the patient in the same order of frequency as would be the tablets.

Example 6 Should a solution be preferred as a dosage form for therapeutic administration then both aqueous and hydroalcohol-ic solutions may be prepared. The preparation of an aqueous solution is accomplished by dissolving the appropriate amount of the active material in simple syrup and adding flavoring and coloring agents, if desired. The preparation of hydroalcoholic solutions is achieved by simple solution of the active material in the desired vehicle which may consist of from 10 to 30 percent of alcoi101 and water. It is desirable to maintain the concentration of active material per unit dose (teaspoonful) of drum 25 to 50 mg. of active material whether the aqueous syrup solutions are used or the hydroalcoholic vehicles are utilized.

Example 7 Solutions for injection may also be prepared by dissolving the appropriate quantity of the active material in sterile water for injection, maintaining an aseptic technique throughout. The solution may be sterilized through the process of bacteriol-ogic filtration and filled into sterile glass ampules so that each cc. contains from 25 to 50 mg. of active material. The solution may be administered by either intravenous or intramuscular injection, in accordance with the patients needs, utilizing the well-known precautions common to this method of administration.

Example 8 When it is desired to take advantage of the different times of action of the amide base and/ or its acid addition salts, on the one hand and the salt on the other, the two may be combined in a tablet or any of the other dosage forms mentioned above in unit dosages so that the combined active material equals 25 to 50 mg. Ordinarily 50 percent of each group is preferred, but if the action desired calls for more emphasis on the quicker action of one or the other the percentage mixture may be varied.

What is claimed is:

1. A compound selected from the group consisting of the nitric acid ester of bis-(beta-hydroxyethyl)-amine nieotinate, bis-nitric acid ester of nicotinic acid-bis-(beta hydroXyethyD-amide and the pharmacologically acceptable acid addition salts of the last mentioned compound.

2. The nitric acid ester of bis-(beta-hydroxyethyl)- amine nicotinate.

3. Bis-nitric acid ester of nicotinic acid-bis-(beta-hydroxyethyl) amide.

4. Bis-nitric acid ester of nicotinic acid-bis-(betabydroxyethyD-amide hydrogen chloride.

5. The bis-nitric acid ester of nicotinic acid-bis-(betahydroxyethyl) -amide hydrogen bromide.

References Cited in the file of this patent UNITED STATES PATENTS 2,688,617 Hein et al. Sept. 7, 1954 2,767,192 Ofle et al. Oct. 16, 1956 2,776,923 N-ishizawa Jan. 8, 1957 2,834,786 Mueller May 13, 1958 2,890,984 Sahyun June 16, 1959 2,900,388 Tien Aug. 18, 1959 2,947,741 Ferguson Aug. 2, 1960 FOREIGN PATENTS 904,534 Germany Feb. 18, 1954 OTHER REFERENCES Karrer: Org. Chemistry, page 131 (1950). Drefahl et al.: Chem. Ber, volume 87, pages 1628-31 (1954). 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE NITRIC ACID ESTER OF BIS-(BETA-HYDROXYETHYL)-AMINE NICOTINATE, BIS-NITRIC ACID ESTER OF NICOTINIC ACID-BIS-(BETAHYDROXYETHYL)-AMIDE AND THE PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS OF THE LAST MENTIONED COMPOUND. 